According to the Christopher and Dana Reeve Foundation there are more than 1 million people with spinal cord injury (SCI) in the US. Developing strategies to promote regeneration and functional recovery after SCI has been a long and challenging goal. Although our lab was the first to recognize the critical role of sulfated proteoglycans in regeneration failure, the mechanisms by which the cells that produce this family of inhibitory extracellular matrix molecules block regeneration is largely unknown. Regenerating, albeit dystrophic, axons continually and tightly associate with a cohort of precursor cells in the core of the lesion that produce what is thought to be a potently inhibitory proteoglycan called NG2. The role of these NG2 cells and what has been purported to be a major proteoglycan in regeneration failure has become highly controversial. Our proposed studies will reveal for the first time how such highly preferred growth upon the surface of these cells results in an adhesive entrapment phenomenon that is likely to be a critical determinant in regeneration failure. Our proposed studies will also build upon the exciting discovery of a family of receptors on neurons that mediate, we propose via overly strong adhesive mechanisms, the inhibitory actions of CSPGs. Understanding in depth the complicated cellular and molecular interactions that lead to long term entrapment of axons within the glial scar will allow us to devise improved techniques for blocking or overcoming these untoward interactions and help in the search for strategies to stimulate robust regeneration beyond the glial scar.) PUBLIC HEALTH RELEVANCE: The glial scar that develops after many forms of CNS trauma is a major obstacle to axon regeneration and functional recovery because of the production by certain reactive glial cells in the vicinity of the lesion of a family of potently inhibitory extracellular matrix molecules known as the chondroitin sulfate proteoglycans (CSPGs). Our exciting discovery with the John Flanagan lab of the first known receptors on neurons that mediate the inhibitory effects of these molecules has opened the door to the production of specific blocking peptides and knockout mice that can be used to test the effect of genetic ablation or pharmacological manipulation of these receptors on axon regeneration. Our exciting preliminary data also suggest for the first time how one critical CSPG, produced by a particular population of precursor cells in the lesion core, the NG2 glia, actually function to block regeneration by creating a state of dystrophy and entrapment of the would-be regenerating axon. Our proposed studies will shed light not only on the fundamental mechanisms of regeneration failure but also test new and potentially therapeutic strategies to foster regeneration after spinal cord injury.)